The field of the invention is novel diphenylethylene compounds and their use for treatment of diabetes.
Extracts of the leaves, flowers, and gum of the tree Pterocarpus marsupium Roxb. (Leguminosae), also known as the Indian Kino Tree, have been used traditionally for the treatment of diarrhea, toothaches, fever and urinary and skin infections. Extracts of the bark have been long regarded as useful for the therapy of diabetes. Hypoglycemic activity of a naturally occurring pterostilbene, trans-1-(3,5-dimethoxyphenyl)-2-(4-hydroxyphenyl)-ethylene, isolated from the heartwood of pterocarpus marsupium as been reported by Manickam et al., J. Nat. Prod., 1997, 60:609-610. However, this pterostilbene is water insoluble and has not been shown to be efficacious in the treatment of diabetes, particularly in instances where insulin is present but inactive. The cause of diabetes is yet unknown, although both genetics and environment appear to be factors.
Insulin dependent (Type I) and non-insulin dependent (Type II) are the types of diabetes. Type I is an autonomic immune disease in which the responsible autoantigen is still unknown. Patients of Type I need to take insulin intravenously to survive. However, Type II diabetes, the more common form of the disease, is a metabolic disorder resulting from the body""s inability to make a sufficient amount of insulin or to properly use the insulin that is produced within the body. Insulin secretion and insulin resistance are considered the major defects, however, the precise genetic factors involved in the mechanism remain unknown.
Patients with diabetes usually have one or more of the following defects: less production of insulin by the pancreas; over secretion of glucose by the liver; impairment of glucose uptake by the skeletal muscle; defects in glucose transporters; desensitation of insulin receptors; and defects in the metabolic breakdown of polysaccharides. Other than the intravenous application of insulin, there are four classes of oral hypoglyceric agents in use.
As is apparent from the above table, each of the current agents available for use and treatment of diabetes has certain disadvantages. Accordingly, there is a continuing interest in the identification and development of new agents, particularly, water soluble agents which can be orally administered, for the use of treatment of diabetes.
Besides the pterostilbene discussed above, (xe2x88x92)-epicatechin, has also been isolated from pterocarpus marsupium by Sheehan et al., J. Nat. Prod., 1983, 46:232, and has been reported as having a hypoglycemic effect. See also Chakravarthy et al., Life Sciences, 1981, 29:2043-2047. Other phenolic type compounds have been isolated from pterocarpus marsupium by Maurya et al., J. Nat. Prod., 1984, 47:179-181; Jahromi et al., J. Nat. Prod., 1993, 56:989-994; and Maurya et al., Heterocycles, 1982, 19:2103-2107.
A class of novel diphenylethylenes is provided having the following formula I. 
wherein R is hydrogen or xe2x80x94CO2Z, Z is hydrogen or a cation;
and R1, R2 and R3 are each independently H, xe2x80x94OH or xe2x80x94OR4, wherein R4 is linear or branched alkyl of 1-12 carbon atoms; with the proviso that when R is hydrogen and R2xe2x95x90R3xe2x95x90xe2x88x92OMe, then R1 is not xe2x80x94OH. The configuration around the double bond may be E or Z.
A novel class of styrenes is also provided of the formula II 
wherein R5 is hydrogen or methyl; R6 and R7 are independently hydrogen or OMe; R8 is hydrogen or hydroxy. The configuration around the double bond may be E or Z.
Pharmaceutical compositions of compounds of the formula I or II are provided for treatment of diabetes comprising of therapeutically effective amount of the compound in a physiologically acceptable carrier.
A method of treating diabetes is also provided comprising step of orally administering to a subject suffering from a diabetic condition a therapeutically effective amount of a compound of formula I or II.